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Biomedical subjects

M Aiach

Publications and source records attributed to M Aiach.

At least 91 records · Page 5Linked to original sources
PubMed1996

First case of sporadic protein S deficiency due to a novel candidate mutation, Ala 484-->Pro, in the protein S active gene (PROS1).

In a series of 16 propositi with symptomatic protein S deficiency and a protein S gene mutation, we identified a sporadic case of a novel mutation that probably affects gene expression. The mutation, a G to C transversion leading to the substitution of Ala 484 by Pro, was not found in the protein S gene of the patient's parents. Transmission of the paternal and maternal protein S alleles was apparently normal, on the basis of the frequent polymorphism in exon XV. We also checked the transmission of chromosomal material by analysing protein C gene polymorphisms, beta-globin gene frameworks and four variable number of tandem repeats (VNTRs). By combining the results of these analyses, we were able to rule out nonpaternity and to confirm the de novo nature of the mutation.

Alanine↗
PubMed1996

[Hirudin: the relative failure of a very promising molecule].

Hirudin is a peptide of 65 aminoacids extracted from the leech which very specifically inhibits the action of thrombin. Molecular engineering techniques have made it available for therapeutic usage. Experimental data would suggest that hirudin was the drug of choice for the prevention of coronary thrombosis and recurrences, an indication where heparin is not always effective. Despite well organised studies of tolerance and dosage, three large scale clinical trials have had to be interrupted because of a high incidence of severe bleeding complications. The therapeutic margin of hirudin is therefore as low as that of heparin. The initial results of trials using lower doses have not shown hirudin to be effective than heparin in the prevention of critical events in the long term. The reasons for this relative failure are two-fold: either hirudin and molecules with similar modes of action such as Hirulog are less active in vivo than in vitro, possibly due to the fact that they block the activation of the C protein, a powerful natural antithrombotic mechanism, or, the target of hirudin: thrombin, does not play the fundamental role attributed to it in arterial thrombosis. The good results observed with molecules which inhibit platelet aggregation would suggest a dominant role of the platelets.

Anticoagulants↗
PubMed1995

The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency.

A Ser 460 to Pro mutation of protein S (PS), involving a T to C transition in exon XIII of the protein S alpha (PROS1) gene and known as the Heerlen polymorphism, was found in 16 of 85 symptomatic patients with PS deficiency (18.8%) and only 1 of 113 healthy subjects (0.8%). Another frequent polymorphism was described in exon XV of the PROS1 gene, in the codon for Pro 626 (CCA/CCG). We found that Heerlen polymorphism was associated with allele CCA and not with allele CCG, suggesting a probable transmission by a common ancestor. Most subjects bearing the Ser 460 to Pro mutation were deficient in free PS, but had normal total PS levels. Normal levels of the C4b-binding protein (C4b-BP) isoform containing a beta chain (C4b-BP beta +) ruled out increased C4b-BP beta + as a cause of the free-PS deficiency. The binding curves of the mutated (Heerlen) PS on C4b-BP immobilized on microplates were biphasic, suggesting that one molecule of C4b-BP can bind two molecules of Heerlen PS. Because normal PS binds to C4b-BP with 1:1 stoichiometry, this may explain the free-PS deficiency observed in patients carrying the Ser 460 to Pro mutation.

Carrier Proteins↗
PubMed1995

Identification of mutations in 90 of 121 consecutive symptomatic French patients with a type I protein C deficiency. The French INSERM Network on Molecular Abnormalities Responsible for Protein C and Protein S deficiencies.

By studying the protein C gene of 121 consecutive patients with symptomatic type I protein C deficiency, we detected 55 different candidate mutations in 90 cases. The mutations, 76% of which were missense changes, were distributed throughout the gene. More than half the missense mutations involved Cys, Phe, Pro, or Gly, amino acids known to affect the structure of the polypeptide chain by various mechanisms. Thus, 40% of protein C deficiencies may be caused by polypeptide chain instability rather than a lack of expression of the mutated allele; this may also account for phenotypic heterogeneity. Seventeen of the 55 different mutations were found in apparently unrelated families. Half the French families we studied bore one of these 17 mutations. The wide variety of mutations suggests that both sporadic cases and a founder effect contribute to the spectrum of protein C mutations in a given population. The differences in both unique and recurrent mutations in French and Dutch populations-the only large population samples so far studied-support this hypothesis.

Base Sequence↗
PubMed1995

Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM.

Because multiple risk factors in one patient may increase the clinical expression of thrombophilia, we assessed the presence in protein C-deficient patients of the factor V Arg 506 Gln mutation responsible for activated protein C resistance. Using a strategy allowing rapid screening of factor V exon 10, we studied 113 patients with protein C deficiency and 104 healthy volunteers. We detected the Arg 506 Gln mutation in 15 patients (14%) and in one healthy subject (1%). We identified a previously unpublished sequence variation leading to an Arg 485 Lys substitution in three normal subjects and seven protein C-deficient patients. A significant difference in the allelic frequency of the Arg 506 Gln factor V mutation was found between protein C-deficient patients heterozygous for an identified protein C mutation (n = 84; allelic frequency, 4.8%) and protein C-deficient patients with no identified mutation in the protein C gene coding regions (n = 25; allelic frequency, 14%). The results demonstrate that a significant subset of thrombophilic patients has multiple genetic risk factors although additional secondary genetic risk factors remain to be identified for the majority of symptomatic protein C-deficient patients.

Adolescent↗
PubMed1995

Amino acids 225-235** of the protein C serine-protease domain are important for the interaction with the thrombin-thrombomodulin complex.

Protein C (PC) is a vitamin K-dependent zymogen that inactivates factors Va and VIIIa after its activation by thrombin complexed to thrombomodulin. We characterized a monoclonal antibody (mAb) against PC, whose only influence on PC functions was to inhibit PC activation by the thrombin-thrombomodulin complex. It recognized an epitope in the PC heavy chain, the conformation of which is calcium-dependent. The mAb did not recognize a natural PC variant that was not activated by the thrombin-thrombomodulin complex (mutation R229Q) and did recognize a synthetic peptide corresponding to PC amino acids 225-235 in an Elisa assay. The peptide inhibited PC activation by the thrombin-thrombomodulin complex. These data confirm that the calcium-binding loop of the serine-protease domain is involved in the interaction of PC with the thrombin-thrombomodulin complex.

Amino Acid Sequence↗
PubMed1995

Human thrombin variable region 1, including E39, is involved in interactions with alpha 1-antitrypsin M358R and protein C.

We used an antithrombin autoantibody (IgG D), the epitope of which encompasses ABE1 and amino acids located within variable region 1, to study thrombin interactions with R358 alpha 1-AT and protein C. IgG D inhibited the thrombin interaction with R358 alpha 1-AT, while hirugen had no effect, indicating that the interaction of R358 alpha 1-AT with thrombin may involve the VR1 subsite. We also obtained evidence that VR1 may be involved in the activation of protein C by thrombin in the absence of thrombomodulin. Moreover, IgG D attenuated the inhibitory effect of calcium ions during protein C activation by thrombin, probably by masking E39 within the VR1 site.

Amino Acid Sequence↗
PubMed1995

Protein C infusion in a patient with inherited protein C deficiency caused by two missense mutations: Arg 178 to Gln and Arg-1 to His.

This paper reports the case of an adult patient with severe protein C(PC) deficiency. She had the first deep vein thrombosis when she was 14 years old and developed skin necrosis when oral anticoagulant treatment was started. The same sequence of thrombotic complications recurred several times. Analysis of the PC gene coding sequences allowed two mutations (Arg-1 to His and Arg 178 to Gln) to be identified in this compound heterozygote. Oral anticoagulant treatment during PC concentrate infusion and low-molecular-weight heparin administration was successful and uncomplicated.

Arginine↗
PubMed1995

A rapid screening method for the factor V Arg506-->Gln mutation.

This study compared a rapid method to detect the nucleotide mutation 1691 G-->A, responsible for the factor V Arg506-->Gln substitution, with a previously established denaturing gradient gel electrophoresis (DGGE) technique in 136 patients with unexplained thrombosis. The new method comprises amplification of the factor V gene exon 10 with a modified oligonucleotide, permitting the introduction of a cleavage site for the restriction endonuclease HindIII in the fragments bearing the mutation. This simple, rapid, inexpensive and nonisotopic method gave the same results as the DGGE method in all subjects tested.

Base Sequence↗
PubMed1995

Pharmacokinetic study of the low-molecular-weight heparin fraxiparin in patients with nephrotic syndrome.

We studied the pharmacokinetics of the low-molecular-weight heparin (LMWH) Fraxiparin in 6 patients with the nephrotic syndrome. Maximal plasma anti-Xa activity was obtained 5 h after a subcutaneous injection of 60 IU anti-Xa/kg. Anti-Xa activity was no longer detectable 24 h postinjection. These results are similar to those obtained with the same dosage in other clinical settings. The biological response to a daily subcutaneous injection of 60 IU anti-Xa/kg was studied for 8 days. No cumulative effect was observed. All the patients had an abnormal activation state of hemostasis mechanisms before treatment, as shown by high prothrombin fragment 1 + 2 and D-dimer levels, which were not decreased by Fraxiparin. It remains to be determined whether a higher dosage of LMWH might attenuate the hypercoagulability in these patients.

Adult↗